The present invention relates to short peptides, two to four amino acids in length, to be used as antihypertensive agents.
Hypertension is a serious health problem of epidemic proportions. It is estimated that 20% of the adult population of North America have systemic arterial pressures above the accepted normal range. A few direct causes of hypertension, such as pheochromocytoma and primary hyperaldosteronism, are amenable to direct therapeutic intervention. These instances are not the norm. In general, pharmacologic treatment of hypertension involves treating the symptom. Therapy is directed only to a correction of the abnormal pressure. Yet, it is now clear that such therapy can favorably affect prognosis and thus greatly decrease the risk of death due to cardiovascular disease in the affected person.
Essential, or primary, hypertension is a poorly defined condition that is diagnosed by exclusion. It is not known whether hypertension is a disease per se or simply the upper end of a continuous spectrum of blood pressures in the population. In both normotensive and hypertensive individuals, vascular tone is controlled by sympathetic nerve fibers. Even in normotensive individuals, reduction of the vascular tone can reduce the blood pressure. Thus, abnormal sympathetic nerve function is probably not responsible for the increased peripheral resistance that characterizes primary hypertension.
Pharmacologic therapy of hypertension has generally been directed at promoting salt excretion (diuretics) and decreasing vascular tone by both direct (direct vasodilators) and indirect (adrenegic blocking agents) means. Diuretics are an effective means of reducing overall blood volume and thereby reduce blood pressure, yet their use, particularly in moderate to severe hypertension, is generally secondary to other agents. Diuretics also tend to deplete serum potassium, which can have serious consequences in the cardio-compromised patient.
The indirect vasodilators are probably the most extensively used agents for mild to moderate hypertension. These agents, for the most part, act on some part of the sympathetic nervous system. Propranolol, a beta adrenergic blocker, is widely used in this country to varying degrees of success. Propranolol alone, though, provides poor control of hypertension. Such therapy can also lead to various uncomfortable side effects including a prolonged reduction in cardiac output accompanied by depression, impotence, and a pronounced lethargy. Other indirect acting agents, including Guanethidine, Pargyline, Methyldopa, Reserpine, Clonidine, and the ganglionic blockers, have also displayed varying degrees of success with numerous side effects and untoward reactions.
Similarly, problems with side effects are common with long term use of drugs that act directly on the vascular smooth muscle. Diazoxide is both hyperuricemic and hyperglycemic. Nitroprusside is a powerful vasodilator but its effects are transient and the drug must be given by continuous infusion. Hydralazine is used regularly even though the incidence of untoward reactions is very high.
In all of these agents, the main problems facing the physician are efficacy and side effects. In the area of antihypertensives, even minor side effects can result in the serious problem of patient non-compliance. In terms of efficacy, the direct acting agents appear to offer the best control of the hypertensive state yet their toxicities and other limitations tend to decrease their usefulness, particularly in mild to moderate cases. It is in the interest of medical science, therefore, to develop new approaches to the treatment of hypertension.